Structural and Biochemical Insights into the Activation Mechanisms of Germinal Center Kinase OSR1

	Structural and Biochemical Insights into the Activation Mechanisms of Germinal Center Kinase OSR1
	Li, CC; Feng, M; Shi, ZB; Hao, Q; Song, XM; Wang, WJ; Zhao, Y; Jiao, S; Zhou, ZC
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2014
卷号	289 期号:52 页码:35969-35978
通讯作者	Jiao, S (reprint author), Inst Biochem & Cell Biol, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,jiaoshi@sibcb.ac.cn ; zczhou@sibcb.ac.cn
英文摘要	The oxidative stress-responsive 1 (OSR1) kinase belongs to the mammalian STE20-like kinase family. OSR1 is activated by with no lysine [K] (WNKs) kinases, and then it phosphorylates cation-coupled Cl-cotransporters, regulating ion homeostasis and cell volume in mammalian cells. However, the specific mechanisms of OSR1 activation remains poorly defined, largely due to its extremely low basal activity. Here, we dissect in detail the regulatory mechanisms of OSR1 activation from the aspects of autoinhibition, upstream kinase WNK, and the newly identified master regulator mouse protein-25 (MO25). Based on our structural and biochemical studies, we propose a "double lock" model, accounting for the tight autoinhibition of OSR1, an effect that has to be removed by WNK before MO25 further activates OSR1. Particularly, the conserved C-terminal (CCT) domain and alpha AL helix act together to strongly suppress OSR1 basal activity. WNKs bind to the CCT and trigger its conformational rearrangement to release the kinase domain of OSR1, allowing for MO25 binding and full activation. Finally, the regulatory mechanisms of OSR1 activation were further corroborated by cellular studies of OSR1-regulated cell volume control through WNK-OSR1 signaling pathway. Collectively, these results provide insights into the OSR1 kinase activation to facilitate further functional study.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	ALANINE-RICH KINASE ; CRYSTAL-STRUCTURE ; STE20-RELATED KINASES ; PROTEIN-KINASES ; SPAK ; WNK1 ; COTRANSPORTERS ; HYPERTENSION ; PATHWAY ; COMPLEX
收录类别	SCI
语种	英语
WOS记录号	WOS:000346897900027
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/275]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Li, CC,Feng, M,Shi, ZB,et al. Structural and Biochemical Insights into the Activation Mechanisms of Germinal Center Kinase OSR1[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2014,289(52):35969-35978.
APA	Li, CC.,Feng, M.,Shi, ZB.,Hao, Q.,Song, XM.,...&Zhou, ZC.(2014).Structural and Biochemical Insights into the Activation Mechanisms of Germinal Center Kinase OSR1.JOURNAL OF BIOLOGICAL CHEMISTRY,289(52),35969-35978.
MLA	Li, CC,et al."Structural and Biochemical Insights into the Activation Mechanisms of Germinal Center Kinase OSR1".JOURNAL OF BIOLOGICAL CHEMISTRY 289.52(2014):35969-35978.